Dantrolene sodium (1-[[5-(p-nitrophenyl)furfurylidene]-amino]hydantoin sodium salt) is described in U.S. Pat. No. 3,415,821, incorporated herein by reference in its entirety. It can be used as a skeletal muscle relaxant particularly in controlling the manifestations of clinical spasticity resulting from upper neuron disorders (Physicians' Desk Reference, 36th Edition, 1982). It is also used in the prevention and treatment of malignant hyperthermia in humans (Friesen et al., Can. Anaesth. Soc. J. 26:319-321, 1979).
In connection with the use of dantrolene sodium in hyperthermic crisis it was observed that there was an elimination of the arrhythmias accompanying such crisis [Salata et al., Effects of Dantrolene Sodium on the Electrophysiological Properties of Canine Cardiac Purkinje Fibers, J. Pharmacol. Exp. Ther. 220(1): 157-166 (January) 1982], incorporated herein by reference in its entirety. Dantrolene sodium is useful as a cardiac antiarrhythmic agent in hypothermic and normothermic warm-blooded animals as described in U.S. Pat. No. 4,543,359, incorporated herein by reference in its entirety.
It is also known that dantrolene sodium prevents or reduces arrhythmia in hypothermic and normothermic warm-blooded animals. In particular, dantrolene sodium is effective in the treatment of supraventricular tachycardias, in suppressing slow responses in infarcted tissues and in abolishing ventricular premature beats or tachycardias originating in these tissues, and in correcting ventricular rhythm disturbances due to reentry.
Malignant hyperthermia had a mortality rate of nearly 80 percent at the time it was identified in 1960. Treatment consisted only of cooling the patient and treating the specific symptoms, but not the underlying cause. Since 1979, the antidote drug dantrolene sodium has been available for the treatment of malignant hyperthermia and has contributed greatly to a dramatic decline in mortality. The syndrome must be identified and treated early for a successful outcome.
Dantrolene sodium for injection comes as a dry powder that must be dissolved in sterile water prior to injection. Generally, it is supplied in small glass containers containing enough powder to give about 16 to about 20 mg of the active drug.
Although most cases of malignant hyperthermia respond to 2.5-4.0 mg/kg of dantrolene initially, some patients need significantly more to bring the episode under control. In addition, recrudescence is a possibility within the first few days of treatment. Finally, because of the need for continued treatment for at least 48 hours after malignant hyperthermia at a dose of about 1 mg/kg every 4 hours, the Malignant Hyperthermia Association of the United States (MHAUS) recommends that 36 vials be stocked.
The active pharmaceutical ingredient (API) (DS) undergoes slow hydrolytic decomposition in aqueous media. This degradation is accelerated at higher (alkaline) pH values and is enhanced by elevated temperatures. Thus, these conditions should be avoided as much as possible during the production of the final product (DS-IV).
The insolubility of DS in water necessitates its dissolution at a considerably higher pH than its pKa value. The higher pH of its formulation requirement results in: a) the alkaline hydrolysis (loss of potency) of DS, and b) susceptibility of its solution to carbon dioxide during its introduction into vials (filling of vials). The atmospheric carbon dioxide (CO2) appears to interact with the alkaline (e.g., NaOH) content of the filled vials resulting in the reduction of the pH of their solution resulting in a possible undesirable effect in the DS formulation. Thus, the above two phenomena require that the dissolution of the DS (API) at the time of its formulation process and the subsequent introduction of its solution to vials be expedited prior to the commencement of its freeze-drying.
There is a significant need in the art for a satisfactory formulation of dantrolene sodium with greater solubility in a formulation that remains stable enough for practical use.
The present invention teaches the use of a novel organic solvent/water co-solvent system that reduces (a) freezing time of the DS-IV formulation, (b) its freeze-drying time and (c) the reconstitution time of the DS freeze-dried product. A faster reconstitution of the DS-IV product provides a great pharmacotherapeutic advantage in the treatment of patients exhibiting the life-threatening condition of malignant hyperthermia (MH) while undergoing surgery. On average, these patients generally require a rapid intravenous (IV) infusion of nine to ten (9-10) vials of DS-IV product, generally comprising from about 2.5 to about 10 mg/kg patient weight, and each reconstituted with about 60 mL of sterile water for injection (WFI) (See, for example, Merck Manual, 18th Edition, 2006). In many cases, the number of DS-IV vials used ranges from about 10 to about 20 but can be even more. Cases of MH requiring as many as 36 vials of DS-IV have been recorded. The length of time to reconstitute the necessary 10-36 vials (at approximately 1 to 3 min each) creates a significant issue when considering MH death can occur in as short time as 30 min from onset.
Organic co-solvent systems encompass a wide variety of organic solvents (examples: tert butyl alcohol, ethanol, n-propanol, n-butanol, iso-propanol, ethyl acetate, acetone, methyl acetate, methanol, carbon tetrachloride, dimethylsulfoxide, chlorobutanol, cyclohexane, and acetic acid).
The formulation of Caverject™ (Alprostadil) (Pfizer) is an example of sterile marketed injectable product that has been freeze-dried from a TBA-water solution. Table 1 lists several examples of freeze-dried preparations using co-solvent systems.
TABLE 1Examples of compounds freeze-dried with co-solvent system.DrugCo-solvent SystemReferenceAlprostadil20% v/v tert-Teagarden(CAVERJECT ® S.Po.)butanol/wateret al., 1998aAplidine40% v/v tert-Nuijen etbutanol/wateral., 2000Amoxicillin sodium20% v/v tert-Tico Grau etbutanol/wateral., 1988Gentamicin sulfatetert-Butanol/waterBaldi et al.,1994N-Cyclodexyl-N-methyl-4-50% v/v tert-Benjamin(2-oxo-1,2,3,5-butanol/waterand Visor,tetrahydroimidazo-[2.1-b]1989quinazolin-7-yl)oxybutyratnide withascorbic acidCyclohexane 1.2-diaminetert-ButanolTanno etPi(II)al., 1990complexFructose-1.6-diphosphatetert-Butanol/waterSullivanandMarangos,1998Annamycintert-Zou et al.,Butanol/dimethyl1999sulfixide/waterCephalothin sodium5% w/w isopropylKoyama etalcohol/wateral., 1988Cephalothin sodium4% ethanol, 4%Cise andmethanol or 4%Roy, 1981acetone/waterPrednisoloneCarbonDeLuca etacetate/polyglycolic acidtetrachloride/al., 1989ahexafluoroacetonesesquihydrateGabexate mesylateEthanol/waterKamijo etal., 1987Piraubidin hydrochlorideEthanol/waterKaneko etal., 1993Progesterone, coronene,ChlorobutanolTesconi etfluasterone, phenytoinhemihydrate/Dimethylal., 1999sulfonePoly (lactide-co-glycolide)Acetic acidMeredith etal., 1996DioleoylphosphatidylcholineCyclohexaneFelgner andand dioleoylphophatidylEppstein,glycerol1991VecuroniumbromideAcetonitrileJansen,1997Bovine pancreatic trypsinDimethylDesai andinhibitorsulfoxide/1% waterKlibanov,1995